Journal
IMMUNITY
Volume 29, Issue 1, Pages 44-56Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2008.05.007
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Funding
- Intramural NIH HHS [Z01 ES101586-05] Funding Source: Medline
- NCI NIH HHS [R01 CA108454, CA108454] Funding Source: Medline
- NIAID NIH HHS [R01 AI050746-01, R01 AI050746] Funding Source: Medline
- NIAMS NIH HHS [AR050772, R01 AR050772] Funding Source: Medline
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Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3(+) Treg cells was associated in immune responses. Although TGF-beta receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors ROR gamma t and ROR alpha. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3(+) Treg cells. STAT3 regulated Foxp3 downregulation whereas STAT3, ROR gamma, and ROR alpha were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.
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